Oxazole or isoxazole alkylamino ethylene compounds as inhibitors of H-2 histamine receptors

ABSTRACT

The compounds are ethylene derivatives which are inhibitors of histamine activity, in particular, inhibitors of H-2 histamine receptors. A compound of this invention is 1-nitro-2-methylamino-2-[2-((4-methyl-5-imidazolyl)methylthio)-ethylamino]ethylene.

This is a division of application Ser. No. 930,102 filed Aug. 1, 1978,now U.S. Pat. No. 4,220,652 which is a division of application Ser. No.797,160 filed May 16, 1977, now U.S. Pat. No. 4,124,717, which is adivision of application Ser. No. 629,174 filed Nov. 5, 1975, now U.S.Pat. No. 4,046,907, which is a continuation-in-part of application Ser.No. 468,617 filed May 9, 1974, now U.S. Pat. No. 3,953,460.

This invention relates to ethylene derivatives, in particular topharmacologically active 1,1-diaminoethylene derivatives. Thesecompounds are inhibitors of H-2 histamine receptors. In addition, thisinvention relates to pharmaceutical compositions comprising thesecompounds and to methods of inhibiting H-2 histamine receptors withthese compounds. The compounds of the invention can exist as theaddition salts but, for convenience, reference will be made throughoutthis specification to the parent compounds.

It has long been postulated that many of the physiologically activesubstances within the animal body, in the course of their activity,combine with certain specific sites known as receptors. Histamine is acompound which is believed to act in such a way but, since the actionsof histamine fall into more than one type, it is believed that there ismore than one type of histamine receptor. The type of action ofhistamine which is blocked by drugs commonly called "antihistamines" (ofwhich mepyramine is a typical example) is believed to involve a receptorwhich has been designated as H-1. A further group of substances has beendescribed in Black et. al (Nature 1972, 236, 386) which aredistinguished by the fact that they act at histamine receptors otherthan the H-1 receptor and these other receptors have been designated asH-2 receptors. This latter group of substances, to certain of which thepresent invention relates, are thus of utility in inhibiting certainactions of histamine which are not inhibited by the above-mentioned"antihistamines", that is they are H-2 histamine receptor inhibitors.Inhibitors of H-2 histamine receptors are useful, for example, asinhibitors of gastric acid secretion. The substances of this inventionmay also be of utility as inhibitors of certain actions of gastrin. Inthe treatment of certain conditions, for example inflammation, and ininhibiting the actions of histamine on blood pressure, combination ofH-1 and H-2 receptor inhibitors is useful.

The 1,1- diaminoethylene derivatives withwhich the present invention isconcerned may be represented by the following general formula: ##STR1##wherein X and Y, which may be the same or different, are hydrogen,nitro, cyano or SO₂ Ar but are not both hydrogen; R¹ is Hct-(CH₂)_(n)Z(CH₂)_(n) ; R is hydrogen, lower alkyl such as methyl or, being thesame as or different from R'. Hct(CH₂)_(n) Z(CH₂)_(n) ; Z is sulphur ormethylene; m is 0, 1 and 2 and n is 2 or 3 provided that the sum of nand n is 3 or 4; Hct is a nitrogen containing 5 membered heterocyclicring such as imidazole, oxazole, isoxazole, triazole, thiazole,isothiazole or thiadiazole which ring is optionally substituted by loweralkyl, hydroxyl, halogen or amino; and Ar is an aryl group such asphenyl optionally substituted by halogen or methyl, or apharmaceutically acceptable acid addition salt thereof.

It will be appreciated, in the case where R is Hct--(CH₂)_(n)--Z(CH₂)_(n), that Het, m, n and Z need not have the identicalsignificance as in R¹.

Throughout the present specification by the term "lower alkyl" we meanan alkyl group containing from 1 to 4 carbon atoms.

It will be understood that the structure illustrated in Formula I and inFormula I (a) below, is only one of several representations and thatother tautomeric forrms as shown in Formulae II and III and the othergeometrical isomers shown in Formula IV are also covered by the presentinvention. In Formula II to IV and I (a) R¹ represents Het-(CH₂)_(m)-Z(CH₂)_(n). ##STR2##

In a preferred group of compounds of Formula I, R is methyl or Het--Cl₂SCH₂ CH₂, Z is sulphur, m is 1 and n is 2. Most suitably Het isimidazole, thiazole or isothiazole and is optionally substituted bymethyl or halogen.

It is also preferred that X should be nitro and Y should be hydrogen.

Particularly useful compounds are:

1-nitro-2-methylamino-2-[2-(4-methyl-5-imidazolylmethylthio)-ethylamino]ethylene,

1-nitro-2,2-bis-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]ethylene,

1-nitro-2- methylamino-2-[(2-thiazolylmethylthio)ethylamino]ethylene and

1-nitro-2,2-bis-[2-(2-thiazolylmethylthio)ethylamino]ethylene.

A general method for the preparation of the compounds of the presentinvention is shown in the following Scheme 1: ##STR3##

The starting material is a compound of Formula V wherein Q is sulphur oroxygen, preferably sulphur, and R² is lower alkyl such as methyl, oraralkyl, such as benzyl, but is preferably methyl. This may be reactedwith one equivalent of R¹ NH₂ or of RNH₂, R¹ and R have the samesignificance as in Formula I, to give respectively the compounds ofFormulae VI(a) or VI(b) and then reacted with RNH₂ or R¹ NH₂respectively to give the compound of Formula I(a). In the case wherein Ris the same as R¹ the reaction may be carried out in a single step byreacting the compound of Formula V with two equivalents of R¹ NH₂ togive the product of Formula I(b). The reactions described in Scheme 1may be carried out in a suitable solvent, or, particularly when R is thesame as R¹ in the absence of a solvent at a moderately elevatedtemperature, for example at from 90°-150° C.

The intermediate of Formula V wherein Q is sulphur (see Formula V(a) inthe following Scheme 2): ##STR4## may be formed from the substitutedmethane of Formula VII by treatment of the latter with a strong basesuch as sodium hydride or sodium hydroxide and reaction with carbondisulphide to give the compound of Formula VIII. Treatment of thissubstance with an alkyl or aralkyl halide by Formula R² Hal gives therequired compound of Formula V(a).

An alternative method for the preparation of the compounds of FormulaI(a) is shown in scheme 3. ##STR5##

The substituted methane of Formula VII, after treatment with a strongbase such as sodium hydride or sodium hydroxide, may be reacted with anisothiocyanate ester of Formula RN-C-S wherein R is lower alkyl to givethe compound of Formula IX and reaction of this with the alkyl oraralkyl halide of Formula R² Hal results in the compound of Formula Xwherein R is lower alkyl. Further reaction of the compound of Formula Xwith an amine of Formula R¹ NH₂ yields the required compound of FormulaI(a).

A further method which may be used in the preparation of compoundswherein R is hydrogen, X is SO₂ Ar and Y is hydrogen (Formula I (c)) isshown in Scheme 4: ##STR6##

The arylsulphonylacetonitrile of Formula XI wherein Ar has the samesignificance as in Formula I is reacted under anhydrous conditions withethanol and hydrogen chloride to give the iminoether of Formula XII.Treatment of this with a base and subsequent reaction with an amine ofFormula R¹ NH₂ gives the required product of Formula I(c).

It will be appreciated that the final stage of the reactions shown inScheme 1, 3 and 4 may all be expressed by the following reaction:##STR7## wherein D is RNH or R¹ NH; D is R¹ NH₂ or RNH₂ : X, Y, R and R¹have the same significance as in Formula I(a) and Q and R² have the samesignificance as in Formula V, provided that, when it RNH, D must be R¹NH₂.

As stated above, the compounds represented by Formula I have been foundto have pharmacological activity in the animal body as antagonists tocertain actions of histamine which are not blocked by "antihistamines"such as mepyramine. For example they have been found to inhibitselectivly the histamine-stimulated secretion of gastric acid from theperfumed stomachs of rats anesthetised with urethane at doses of from0.5 to 256 micromoles per hilogram intraveously. Similarly, the actionof these compounds of demonstrated by their antagonism to the effects ishistamine on other tissues which, according to the above-mentioned paperof Black et. al., are H-2 receptors. Examples of such tissues areperfused isolated guinea-pig atrium and isolated rat uterus. Thecompounds of the invention have also been found to inhibit the secretionof gastric acid stimulated by pentagastrin or by food.

The level of activity found for the compounds of the present inventionis illustrated by the effective dose range in the anaesthetised rat, asmentioned above of from 0.5 to 256 micromolen per kilogram,intravenously. Many of the compounds of the present invention produce a50% inhibition in this test at a dose of from 1 to 10 micromoles perkilogram.

For therapeutic use, the pharmacologically active compounds of thepresent invention will normally be administered as a pharmaceuticalcomposition comprising as the or an essential active ingredient at leastone such compound in the basic form or in the form of an addition saltwith a pharmaceutically acceptable acid and is association with apharmaceutical carrier therefor. Such addition salts include those withhydrochloric, hydrobromic, hydriodic, sulphuric and maleic acids and mayconveniently be formed from the corresponding bases of Formula I bystandard procedures, for example by treating the base with an acid in alower alkanol.

Pharmaceutical compositions comprising a pharmaceutical carrier and acompound of Formula I or a pharmaceutically acceptable acid additionsalt thereof and methods of inhibiting H-2 histamine receptors whichcomprise administering a compound of Formula I or a pharmaceuticallyacceptable acid addition salt thereof are also objects of thisinvention. The pharmaceutical carrier employed may be, for example,either a solid or liquid. Exemplary of solid carriers are lactose, terraalba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate,stearic acid and the like. Exemplary of liquid carriers are syrup,peanut oil, olive oil, water and the like.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form, or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg to about gm. If a liquid carrier is used, thepreparation may be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampoule, or an aqueous ornonaqueous liquid suspension.

The pharmaceutical compositions are prepared by conventional techniquesinvolving procedures such as mixing, granulating and compressing ordissolving the ingredients as appropriate to the desired preparation.

The active ingredient will be present in the composition in an effectiveamount to inhibit histamine activity. The route of administration may beorally or parenterally.

Preferably, each dosage unit will contain the active ingredient in anamount of from about 50 mg to about 250 mg, most preferably from about100 mg to about 200 mg.

The active ingredient will preferably be administered in equal doses oneto three times per day. The daily dosage regimen will preferably be fromabout 160 mg to about 750 mg, most preferably from about 300 mg to about600 mg.

Other pharmacologically active compounds may in certain cases beincluded in the composition. Advantageously the composition will be madeup in a dosage unit form appropriate to the desired mode ofadministration, for example as a tablet, capsule or injectable solution.

The invention is illustrated but in no way listed by the followingExamples:

EXAMPLE 11,1-Dicyano-2-methylamino-2-[2-((4-methyl-5-imidazolyl)-methylthio)ethylamino]ethyleneMethod (a)

(i) Sodium hydride (50% oil dispersion, 9.6 g) was added portionwise toa solution of malononitrile (13.21 g) in dry dimethylformamide (150 ml).Themixture was stirred at 0° for 10 minutes and then to it was addeddropwise a solution of methyl isothiocyanate (14.62 g) indimethylformamide, maintaining the reaction temperature below 40°. Thedark red solution was stirred for 45 minutes and a solution of methyliodide (28.4 g) in dimethylformamide (25 ml) was then added. Thereaction mixture was stirred vigorously for 20 minutes and then pouredon to crushed ice (500 ml). The crude product (26 g, m.p. 215°) wasfiltered off and taken up in hot ethanol ether (3:1, 600 ml). Filtrationand cooling furnished 1,1-dicyano-2-methylthio-2-methylamino ethylenem.p.119°-120°. Further recrystallisation from water gave a sampleof m.p.120°-121°.

(Found: C, 46.7: H, 4.6: N, 27.1: S, 20.8: C₆ H₇ N₃ S requires: C, 47.0:H, 4.4: N, 27.4: S, 20.9)

(ii) To a stirred suspension of4-methyl-5-[2-aminoethyl)thiomethyl]imidazole (1.71 g) in dryacetonitrile(30 ml) was added 1,1-dicyano-2-methylthio-2-methylaminoethylene (1.53 g).The mixture was stirred at room temperature for onehour and the crude product (1.36 g) was collected. Recrystallizationfrom boiling water furnished1,1-dicyano-2-methylamino-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene,m.p. 133°-135°.

(Found: C, 52.4: H, 5.8: N, 30.5: S, 11.6: C₁₂ H₁₆ N₆ S requires: C,52.2: H, 5.8: N, 30.4: S, 11.6).

Method (b)

A mixture of 1,1-dicyano-2-ethoxy-2-methylaminoethylene (2.27 g) and4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (2.57 g) in acetonitrile(25 ml) was stirred at room temperature for 23 hours. The reactionmixturewas then evaporated to dryness and the residual oilchromatographed on silica gel using acetone as eluent to give, afterremoval of the solvent,1,1-dicyano-2-methylamino-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene,m.p. 131°-133°.

EXAMPLE 21-Nitro-2-ethylamino-2-[2-(4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene

(1) A solution of 4-methyl-5-[2-aminoethyl)thiomethyl]imidazole (1.71 g)in5-butanol (30 ml) was added slowly to a solution of 1-nitro-2,2-bismethylthioethylene (1.66 g) in acetonitrile (20 ml) at room temperature.The solution was heated under reflux for 3 hours, evaporated to drynessand chromatographed on a column of silica gel with elution by anhydrousether (250 ml) followed by acetone (500 ml). The acetone eluate wasconcentrated to low bulk to give1-nitro-2-methylthio-2-[2-(4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene(1.58 g), m.p. 151°-153°. A sample recrystallised from acetonitrile hadm.p. 152°-153°.

(Found: C, 41.4: H, 5.3: N, 19.4: S, 21.8: C₁₀ H₁₆ N₄ O₂ S₂ requires: C,41.7: H, 5.6: N, 19.4: S, 22.2)

(ii) A mixture of1-nitro-2-methylthio-2-[2-(4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene(0.67 g and 33% ethanolic methylamine (4 ml) was heated is a sealed tubeat 70°-80° for one hour. Concentration, followed by purification of theproduct by chromatography on a column of silica gel with acetone aseluant and recrystallisation from acetonitrile furnished1-nitro-2-methylamino-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene(0.30 g), m.p. 141°-3°. Further recrystallisation from isopropanolfurnished a sample m.p. 148°-151°.

(Found: C, 44.5: H, 6.6: N, 25.9: S, 11.4: C₁₀ H₁₇ N₅ O₂ S requires: C,44.3: H, 6.3: H, 25.8: S, 11.8)

EXAMPLE 31-Nitro-2,2-bis[2-(4-methyl-5-imidazolylmethylthio)ethylamino]ethylene

A mixture of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (6.82 g) and1-nitro-2,2-bis-methylthio ethylene (3.30 g) was heated at 140° for2hours. The product was chromatographed on a column of silica gel withelution by ethanolethylacetate (1:4) to separate1-nitro-2-methylthio-2-[2-(4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene(0.56 g. m.p. 150°-151° from ethanol-ether) and furtherelution byethanol-ethyl acetate (3:2) to separate the title compound (6.5 g, m.p.152°-153° from ethanol-ether)

(Found: C, 46.5: H, 6.1: N, 23.6: S, 15.57: C₁₆ H₂₅ N₇ O₂ S₂ requires:C, 46.7; H, 6.1: N, 23.6: S, 15.5%)

EXAMPLE 41-benzenesulphonyl-2-amino-[2-(4-methyl-5-imidazolyl)methylthio)ethylamino]ethylenedihydrochloride

Phenylsulphonyl acetonitrile (14.5 g) was suspended in anhydrous ether(100ml) containing absolute ethanol (3.0 g) and into the stirredsuspension waspassed hydrogen chloride with stirring to a weight gain of6.0 grams. Stirring was continued in the cold for 24 hours and thereaction mixture was then set aside in the cold for 3 days. Thecrystalline iminoether hydrochloride (13.4 g) m.p. 145°-9° wascollected. A solution of this hydrochloride (6.82 g) in aqueouspotassium carbonate wasextracted with ether and the ether extracts driedand concentrated which gave the imino ether as the free base. This wasdissolved in acetonitrile (50 ml) containing4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (5.1 g) and the solutionwas left at room temperature for 24 hours, heated at 50° for 5 hours andfinally heated at reflux for 2 hour. The product was chromatographed ona column of neutral alumina with elution byethanol-ethyl acetate (3:2).The eluate was converted into a picrate which was recrystallised fromnitromethane to afford the title compound as the dipicrate m.p.175°-177°.

(Found: C, 39.8: H, 3.2: N, 17.5: S, 7.9%: C₁₅ H₂₀ N₄ O₂ S₂ 2C₃ H₃ N₃ O₇requires: C, 40.0: H, 3.2: N, 17.3: S, 7.9%) The dipicrate (0.5 g) wasdissolved in aqueous methanol (1:1, 50 ml) and ion-exchanged to chlorideon a column (IRA 401) in the Cl form. The eluate was lyophilised anddissolved in water to provide an aqueous solution of the title compounddihydrochloride (Found: Cl, 16.4% C₁₅ H₂₀ N₄ O₂ S₂ 2HCl requires: Cl,16.7%).

EXAMPLE 52-Amino-1,1-dicyano-2-[2-(4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene

A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (4.1 g) and2-amino-1,1,-dicyano-2-methylthioethylene (2.3 g) in ethanol was heatedunder reflux for 2.5 hours. Concentration followed by chromatographicpurification on a column of silica gel with ethyl acetate as eluentafforded the title compound (1.32 g), m.p. 187°-188°.

(Found: C, 50.2: H, 5.4: H, 31.6: S, 11.7% C₁₁ H₁₄ N₄ S₆ requires: C,50.4: H, 5.4: N, 32.0: S, 11.2%)

EXAMPLE 61-Nitro-2-ethylamino-2-[2-(4-methyl-5-imidazolyl)methylthio]ethylamino-ethylene

Reaction of 1-nitro-2-methylthio-2[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene with ethylamine according to the processofExample 2(ii) yielded the title compound, m.p. 171°-172°.

(Found: C, 46.2; H, 6.7; N, 24.3; S, 11.0% C₁₁ H₁₉ H₅ O₂ S requires: C,46.3; H, 6.7; N, 24.5; S, 11.2%).

EXAMPLE 7 1-Cyano-2-methylamino-2-[2-(4-methyl-5-imidazolyl methylthio)ethylamino]ethylene

4-Methyl-5-[(2-aminoethyl)thiomethyl]imidazole (3.5 g) was added to asolution of 1-cyano-2-ethoxy-2-methylaminoethylene in pyridine (3.1 g)andthe solution was stirred for 5 hours at 100°. The product waschromatographed on a column of neutral alumina with elution bychloroform/ethyl acetate (1:1) to give the title compound as a glass.

The NMR spectrum in CDCl₃, recorded at 60 mHz showed the followingresonances:

    ______________________________________                                        imidazole-2-H: singlet at δ7.46                                                                   integral 1.2 protons:                                                         calculated, 1.0 protons                             imidazole-CH.sub. 2 : singlet at δ3.71                                                            integral 2.0 protons:                                                         calculated 2.0 protons                              S--CH.sub.2 --CH.sub.2 --N:                                                   multiplet at 187-215 H.sub.z                                                                            integral 2.4 protons                                vinylic-H: singlet at δ2.85                                             S--CH.sub.2 --CH.sub.2 --N:                                                   multiplet 145-183 H.sub.z integral 6.07 protons                               --NHCH.sub.3 : singlet at δ2.77                                                                   calculated 6.0 protons                              CH.sub.3 --imidazole: singlet at δ 2.2                                                            The integral was used                                                         as the internal stan-                                                         dard equal to 3.0 pro-                                                        tons                                                ______________________________________                                    

Mass Spectrum: m/e: 251 (Molecular weight: 251).

EXAMPLE 8 1-Nitro-2-methylamino-2-[4-(4-imidazolyl)butylamino]ethylene

(i) A solution of 4-(4-aminobutyl)imidazole (from the dihydrobromide(3.6 g)) and 1-nitro-2,2-bis-methylthioethylene (2.0 g) in acetonitrile(50 ml)was set aside at room temperature for 3 days. The product waschromatographed on a column of silica gel to give1-nitro-2-methylthio-2-[4-(4-imidazolyl)butylamino]ethylene.

(ii) A solution of the methylthio compound (2.0 g) in ethanolicmethylamine(33% w/v, 2 ml) was set aside overnight at room temperatureand then heatedunder reflux for 15 min. From the reaction mixture wasisolated the title compound (1.9 g).

EXAMPLE 91-Nitro-2-methylamino-2-[3-(2-imidazolythio)propylamino]ethylene

By the procedure of Example 8 (i), 2-(3-aminopropylthio)imidazole (fromthedihydrobromide (3.8 g)) is reacted with1-nitro-2,2-bis-methylthioethylene (2.0 g) to give1-nitro-2-methylthio-2-[3-(2-imidazolythio)propylamino]ethylene which,on treatment with methylamine according to the procedure of Example8(ii) gives the title compound.

EXAMPLE 101-Nitro-2-methylamino-2-[2-(2-(4-imidazolyl)ethylthio)ethylamino]ethylene

4-[2-(2-Aminoethylthio)ethyl]imidazole (from the dihydrobromide (4.0 g))isreacted with 1-nitro-2,2-bis-methylthioethylene (2.0 g) by theprocedure ofExample 8(i) and the resultant1-nitro-2-methylthio-2-[2-(2-(4-imidazolyl)ethylthio)ethylamino]ethyleneis treated with methylamine according to the procedure of Example 8(ii)toyield the title compound.

EXAMPLE 11

When 4-bromo-5-[(2-aminoethyl)thiomethyl]imidazole (from thedihydrobromide(4.8 g)) is reacted with1-nitro-2,2-bis-methylthioethylene (2.0 g) according to the procedure ofExample 8(i) and the resultant1-nitro-2-methylthio-2-[2-((4-bromo-5-imidazolyl)methylthio)ethylamino]ethylenetreated with methylamine by the procedure of Example 8(ii) there isproduced1-nitro-2-methylamino-2-[2-((4-bromo-5-imidazolyl)methylthio)ethylamino]ethylene.

EXAMPLE 121-Nitro-2-methylamino-2-[2-((2-amino-4-imidazolyl)methylthio)ethylamino]ethylene

Freshly prepared sodium amalgam (90 g) is added over 75 minutes to astirred solution of serine ethyl ester dihydrochloride (3.0 g) inwater/ethanol (2:1), the temperature being maintained within the rangeof from -12° to -10° and the pH at about 2.5 by the addition of5 Nhydrochloric acid. After a further 45 minutes the mixture is allowedtowarm to 10° and the precipitated free mercury is removed. Cyanamide isadded and the mixture warmed to 50° for 30 minutes, left at 0° for 18hours and evaporated to dryness. After washing with etherto remove anyunchanged cyanamide, the residue is extracted with hot ethanol andheated with hot ethanolic pieric acid. Concentration and cooling of thesolution gives 2-amino-4-hydroxymethylimidazole pierate.

Reaction of 2-amino-4-hydroxymethylimidazole hydrochloride (which isobtained by treating the pierate salt with hydrochloric acid) withcysteamine hydrochloride and reaction of the resulting2-amino-4-[(2-aminoethyl)thiomethyl]imidazole with1-nitro-2,2-bis-methylthioethylene according to the procedure of Example8(i) gives1-nitro-2-methylthio-2-[2-((2-amino-4-imidazolyl)methylthio)ethylamino]ethylene.Finally, reaction with methylamine by the procedure of Example8(ii)produces the title compound.

EXAMPLE 13

In the procedure of Example 4, replacement as starting material ofphenylsulphonylacetonitrile by

(4-chlorophenyl)sulphonylacetonitrile

(3,4-dichlorophenyl)sulphonylacetonitrile

(4-methylphenyl)sulphonylacetonitrile

results in the formation of the following products:

1-(4-chlorobenzene)sulphonyl-2-amino[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene

1-(3,4-dichlorobenzene)sulphonyl-2-amino-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene

1-(4-methylbenzene)sulphonyl-2-amino-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene.

EXAMPLE 14

By using diphenylsulphonylmethane as the starting material in place ofmalononitrile in the procedure of Example 1 (a) (i) there is produced1,1-diphenylsulphonyl-2-methylthio-2-methylamino ethylene and when thisisreacted with 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole accordingto the procedure of Example 1 (a)(ii), the resultant product is1,1-diphenylsulphonyl-2-methylamino-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene.

By the same procedure, starting from

nitroacetonitrile,

phenylsulphonylnitromethane and

phenylsulphonylacetonitrile

the following products may be produced

1-cyano-1-nitro-2-methylamino-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene,

1-nitro-1-phenylsulphonyl-2-methylamine-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethyleneand

1-cyano-1-phenylsulphonyl-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene.

EXAMPLE 15

Reaction of1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylenewith an excess of 2-[(2-aminoethyl)thiomethyl]triazole according to theprocedure of Example 3, results in the production of1-nitro-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-2-[2-(2-thiazolylmethylthio)ethylamino]ethylene,m.p. 110°-120° (from acetonitrile).

By the same procedure, reaction of1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylenewith the following compounds

3-[(2-aminoethyl)thiomethyl]isothiazole (prepared by the method ofExample 72),

4-(4-aminobutyl)imidazole,

4-bromo-5-[(2-aminoethyl)thiomethyl]imidazole,

2-(3-aminopropylthio)oxazole (prepared by the method of Example 10),

3-[(2-aminoethyl)thiomethyl]isoxazole (prepared by the method of Example31),

3-[(2-aminoethyl)thiomethyl]-1,2,4-triazole and

2-amino-5-[(2-aminoethyl)thiomethyl]-1,3,4-thiadiazole yieldsrespectively the products:

1-nitro-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-2-[2-(3-isothiazolylmethylthio)ethylamino]ethylene,

1-nitro-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-2-[4-(4-imidazolyl)butylamino]ethylene,

1-nitro-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-2-[2-((4-bromo-5-imidazolyl)methylthio)-ethylamino]ethylene,

1-nitro-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-2-[3-(2-oxazolylthio)propylamino]ethylene,1-nitro-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-2-[2-(3-isoxazolylmethylthio)ethylamino]ethylene,

1-nitro-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-2-[2-(3-(1,2,4)-triazolylmethylthio)ethylamino]ethyleneand

1-nitro-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-2-[2-((2-amino-5-(1,3,4)-thiadiazolyl)methylthio)ethylamino]ethylene.

EXAMPLE 16

When a solution of

1-nitro-2-methylamino-2-[2-(4-methyl-5-imidazolyl)methylthio)ethylamino]ethylenein acetone is treated with ion-exchange resin IRA 400 in thechlorideform the corresponding hydrochloride addition salt is formed.

Similarly, by using the above procedure with ion-exchange resin IRA 400which has been converted to the bromide, iodide and sulphaterespectively the hydrobromide, hydriodide and hydrogen sulphate additionsalts of1-nitro-2-methylamino-2-[2-(4-methyl-5-imidazolyl)methylthio)ethylamino]ethylenemay be produced.

EXAMPLE 17

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        1-Nitro-2-methylamino-2-[2-(4-methyl-5-                                       imidazolylmethylthio)ethylamino]ethylene                                                                150 mg                                              Sucrose                    75 mg                                              Starch                     25 mg                                              Talc                       5 mg                                               Stearic Acid               2 mg                                               ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

EXAMPLE 18

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        1-Nitro-2,2-bis-[2-(4-methyl-5-                                               imidazolylmethylthio)ethylamino]ethylene                                                                200 mg                                              Lactose                   100 mg                                              ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

EXAMPLE 191-Nitro-2-methylamino-2-[3-(2-oxazolylthio)propylamino]ethylene

(i) Hydrochloric acid (90 ml) was added to potassium thiocyanate inethanol(1.8 l.) with stirring. Following filtration from inorganicmaterial, glycollaldehyde (35.9 g) was added and the resulting solutionwas heated under reflux for 24 hours. Concentration, followed by coolingafforded a white solid, which following recystallisation from ethanolafforded oxazole-2-thiol (30 g), m.p. 143°-144°.

(ii) 3-Bromopropylphthalimide (13.4 g) was added to a stirred solutionof sodium ethoxide (from 1.15 g sodium) and oxazole-2-thiol (5.1 g) inethanol (100 ml). The resultant solution was heated under reflux for 2.5hours and concentrated under reduced pressure. The residue wastriturated with water (100 ml) to afford2-(3-phthalimidepropylthio)oxazole (14 g), m.p. 101°. Recrystallisationfrom ethanol gave the pure oxazole, m.p. 102°-103°.

(iii) Hydrazine hydride (5.3 g) was added carefully to a solution of2-(3-phthalimidopropylthio)oxazole (10 g) in ethanol (173 ml) withstirring. The solution was then heated under reflux for 25 minutes.After cooling, and filtration from phthalhydrazide, the filtrate wasconcentrated under reduced pressure and the residue was re-evaporatedwithethanol to yield crude 2-(3-aminopropylthio)oxazole.

(iv) By the procedure of Example 8(i), 2-(3-aminopropylthio)oxazole (2.1g)is reacted with 1-nitro-2,2-bis-methylthioethylene (2.0 g) to give1-nitro-2-methylthio-2-[3-(2-oxazolylthio)propylamino]ethylene (2.1 g)which, on reaction with methylamine by the procedure of Example 8(ii)gives the title product (1.8 g).

EXAMPLE 201-Notro-2-methylamino-2-[3-(4-methyl-2-oxazolylthio)propylamino]ethylene

(i) The reaction of 4-methyloxazole-2-thiol (5.8 g) with3-bromopropylphthalimide (13.4 g) using the conditions described inExample 19 affored 4-methyl-2-(3-phthalimidopropylthio)oxazole (14 g),m.p. 92°-93° (ethanol-ether).

(ii) Treatment of the phthalimide compound (3.0 g) with hydrazine (1.53g) followed by reaction of the product directly with1-nitro-2,2-bis-methylthioethylene (2.2 g) and then with methylamineunderthe conditions described in Example 8 afforded the title product.

EXAMPLE 211-Nitro-2-methylamino-2-[2-((4-methyl-5-oxazolyl)methylthio)ethylamino]ethylene.

(i) Phthalimidoethanethiol (2 g) was added portionwise with stirring toa solution of sodium ethoxide (prepared from 0.23 g of sodium) inethanol (20 ml) at 0° under a nitrogen atmosphere. After stirring at 0°for a further 21/2 hours, the resulting yellow solution was cooled withan ice-salt bath and a solution of 4-methyl-5-chloromethyloxazole (0.86g) in ethanol (5 ml) was added dropwise over 10 minutes. After additionthe mixture was stirred at room temperature overnight, then acidifiedwith ethanolic hydrogen chloride andevaporated to dryness. Addition ofwater precipitated unreacted phthalimidoethanethiol (0.6 g) which wasremoved by filtration. The filtrate was concentrated and basified withaqueous sodium bicarbonate solution to furnish a white precipitatewhich, on recrystallisation from aqueous ethanol, gave4-methyl-5-[(2-phthalimidoethyl)thiomethyl]oxazole (0.75 g). A stirredmixture of this phthalimide derivative (0.62 g) in aqueous hydrobromicacid (40 ml. 18%) was heated under reflux overnight. After cooling to0°, the resulting clear solution was filtered and the filtrateevaporated to dryness. Recrystallisation of the residue from ethanolgave 4-methyl-5-[(2-aminoethyl)thiomethyl]oxazole dihydrobromide (0.52g).

(ii) Reacting 4-methyl-5-[(2-aminoethyl)thiomethyl]oxazole with1-nitro-2,2-bis-methylthioethylene and then with methylamine by theprocedure of Example 8 gives the title product.

EXAMPLE 22

Using 5-(2-chloroethyl)-4-methyloxazole as starting material in theprocedure of Example 21 the product is1-nitro-2-methylamino-2-[2-(2-(4-methyl-5-oxazolyl)ethyl)thioethylamino]ethylene.

Also, using 2-amino-5-(2-chloroethyl)oxazole (prepared by reacting2-amino-5-(2-hydroxyethyl)oxazole with thionyl chloride) in theprocedure of Example 21 gives1-nitro-2-methylamino-2-[2-(2-(2-amino-5-oxazolyl)ethyl)thioethylamino]ethylene.

EXAMPLE 231-Nitro-2-methylamino-2-[2-((5-chloro-2-methyl-4-oxazolyl)methylthio)ethylamino]ethylene

Reduction of 5-chloro-2-methyl-4-oxazolecarboxylic acid with diborane tothe corresponding 4-hydroxymethyl compound, conversion of this to the4-chloromethyl compound and use of this chloromethyl compound as thestarting material in the procedure of Example 21 gives the titlecompound.

EXAMPLE 241,1-Dicyano-2-[3-(2-oxazolylthio)propylamino]-2-[2-((4-methyl-5-imidazolyl)methylthio]ethylaminoethylene

(i) Reaction of malononitrile with carbon disulphide in the presence ofalcoholic sodium methoxide and treatment of the product with methyliodide(see Berichte, 1962, 95, 2861) yields1,1-dicyano-2,2-bis-methylthioethylene.

(ii) Reaction of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole with1,1-dicyano-2,2-bis-methylthioethylene by the procedure of Example 8(i)yields1,1-dicyano-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene.

(iii) Reaction of this methylthio compound with2-(3-aminopropyl)thiooxazole by the procedure of Example 1(a)(ii) givesthe title compound.

EXAMPLE 251-Cyano-2-[3-(2-oxazolythio)propylamino]-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene

Reaction of 1-cyano-2,2-bis methoxyethylene (J.A.C.S., 1949, 71, 47)with 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole by the procedure ofExample8(i) yields1-cyano-2-methoxy-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene.

(ii) Reaction of this methylthio compound with2-(3-aminopropylthio)oxazoleby the procedure of Example 1(a)(ii) givesthe title compound.

EXAMPLE 26

(i) Reaction of methylphenylsulphone with carbon disulphide understrongly basic conditions and treatment of the product with methyliodideyields 1-benzenesulphonyl-2,2-bis-methylthioethylene.

(ii) When 1-benzenesulphonyl-2,2-bis-methylthioethylene is reacted inthe procedure of Example 8(i) with:

5-[(2-aminoethyl)thiomethyl]-1-methylimidazole the product is:

1-benzenesulphonyl-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene.

(iii) Reaction of this methylthio compound with2-(3-aminopropylthio)oxazole by the procedure of Example 1(a)(ii) gives:

1-benzenesulphonyl-2-[3-(2-oxazolylthio)propylamino]-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene.When, in place of methylphenylsulphone, the following sulphones are usedas the starting materials:

methyl-(4-chlorphenyl)sulphone,

methyl-(3,4-dichlorophenyl)sulphone and

methyl-(4-methylphenyl)sulphone,

the following products are produced respectively:

1-(4-chlorobenzene)sulphonyl-2-[3-(2-oxazolylthio)propylamino]-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene,

1-(3,4-dichlorobenzene)sulphonyl-2-[3-(2-oxazolylthio)propylamino]-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethyleneand

1-(4-methylbenzene)sulphonyl-2-[3-(2-oxazolylthio)propylamino]-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-ethylene.

EXAMPLE 271-Nitro-2-ethylamino-2-[3-(2-oxazolylthio)propylamino]ethylene

Reaction of1-nitro-2-methylthio-2-[3-(2-oxazolylthio)propylamino]ethylene (seeExample 19(iv)) with ethylamine by the procedure of Example 8(ii) givesthe title product.

EXAMPLE 28

Reaction of1-nitro-2-methylthio-2-[3-(2-oxazolylthio)propylamino]ethylene in theprocedure of Example 3 with an excess of the following compounds:

2-(3-aminopropylthio)oxazole,

3-[(2-aminoethyl)thiomethyl]isoxazole prepared by the method of Example30),

3-[(2-aminoethyl)thiomethyl]-1,2,4-triazole,

2-[(2-aminoethyl)thiomethyl]thiazole,

3-[(2-aminoethyl)thiomethyl]isothiazole (prepared by the method ofExample 72) and

2-amino-5-[(2-aminoethyl)thiomethyl]-1,3,4-thiadiazole gives thefollowing products respectively:

1-nitro-2,2-bis-[3-(2-oxazolylthio)propylamino]ethylene,

1-nitro-2-[3-(2-oxazolylthio)propylamino]-2-[2-(3-isoxazolylmethylthio)ethylamino]ethylene,

1-nitro-2-[3-(2-oxazolylthio)propylamino]-2-[2-(3-(1,2,4)-triazolylmethylthio)ethylamino]ethylene,

1-nitro-2-[3-(2-oxazolylthio)propylamino]-2-[2-(2-thiazolylmethylthio)ethylamino]ethylene,

1-nitro-2-[3-(2-oxazolylthio)propylamino]-2-[2-(3-isothiazolylmethylthio)ethylamino]ethyleneand

1-nitro-2-[3-(2-oxazolylthio)propylamino]-2-[2-((2-amino-5-(1,3,4)-thiadiazolyl)methylthio)ethylamino]ethylene.

EXAMPLE 29

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        1-Nitro-2-[3-(2-oxazolylthio)propylamino]-2-                                  [2-((4-methyl-5-imidazolyl)methylthio)ethyl-                                  amino]ethylene            150 mg                                              Sucrose                    75 mg                                              Starch                     25 mg                                              Talc                       5 mg                                               Stearic Acid               2 mg                                               ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 30

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        1-Nitro-2-[3-(2-oxazolylthio)propylamino]-2-                                  2-((4-methyl-5-imidazolyl)methylthio)-                                        ethylamino]ethylene       200 mg                                              Lactose                   100 mg                                              ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 311-Nitro-2-methylamino-2-[2-(3-isoxazolylmethylthio)ethylamino]ethylene

(i) A solution of 3-chloromethylisoxazole (5.8 g) and cysteaminehydrochloride (6.25 g) in aqueous hydrobromic acid (48%, 100 ml) washeated under reflux for 6 hours. Concentration in the presence of waterand subsequently n-propanol, followed by recrystallisation of theresidue from isopropyl alcohol-ethanol afforded3-[(2-aminoethyl)thiomethyl]isoxazole hydrobromide, m.p. 131°-133°.

(Found: Br, 33.6: S, 13.7. C₆ H₁₀ N₂ OS.HBr requires: Br, 33.4: S,13.4).

(ii) By the procedure of Example 8(i),3-[(2-aminoethyl)thiomethyl]isoxazole (from the hydrobromide (3.7 g)) isreacted with 1-nitro-2,2-bis-methylthioethylene (3.5 g) to give1-nitro-2-methylthio-2-[2-(3-isoxazolylmethylthio)ethylamino]ethylene(3.6g) which, on reaction with methylamine by the procedure of Example8(ii) gives the title product (3.0 g).

EXAMPLE 32

Using the following chloromethylisoxazoles (prepared from thecorrespondinghydroxymethylisoxazoles by treatment thereof with thionylchloride) as starting materials in the procedure of Example 31:

3-chloromethyl-5-methylisoxazole,

3-bromo-5-chloromethylisoxazole and

4-(2-chloroethyl)-5-methylisoxazole

the products are, respectively:

1-nitro-2-methylamino-2-[2-(5-methyl-3-isoxazolylmethylthio)ethylamino]ethylene,

1-nitro-2-methylamino-2-[2-(3-bromo-5-isozazolylmethylthio)ethylamino]ethyleneand

1-nitro-2-methylamino-2-[2-(2-(5-methyl-4-isoxazolyl)-ethylthio)ethylamino]ethylene.

EXAMPLE 33

Using, in the procedure of Example 31, 3-mercaptopropylamine in place ofcysteamine, the product is1-niro-2-methylamino-2-[3-(3-isoxazolylmethylthio)propylamino]-ethylene.

EXAMPLE 341,1-Dicyano-2-methylamino-2-[2-(3-isoxazolylmethylthio)ethylamino]ethylene

By the procedure of Example 1(ii), reacting3-[(2-aminoethyl)thiomethyl]isoxazole with1,1-dicyano-2-methylthio-2-methylaminoethylene gives the title compound.

EXAMPLE 351-Cyano-2-methylamino-2-[2-(3-isoxazolyimethylthio)ethylamino]ethylene.

By the same procedure as Example 7, using as starting material3-[(2-aminoethyl)thiomethyl]isoxazole, the title compound is prepared.

EXAMPLE 36

Reaction of 3-[(2-aminoethyl)thiomethyl]isoxazole by the procedure ofExample 4 with the following acetonitriles:

phenylsulphonylacetonitrile,

(4-chlorophenyl)sulphonylacetonitrile,

(3,4-dichlorophenyl)sulphonylacetonitrile and

(4-methylphenyl)sulphonylacetonitrile

results in the formation of the following products, respectively:

1-benzenesulphonyl-2-amino-2-[2-(3-isoxazolylmethylthio)ethylamino]ethylene

1-(4-chlorobenzene)sulphonyl-2-amino-2-[2-(3-isoxazolylmethylthio)ethylamino]ethylene,

1-(3,4-dichlorobenzene)sulphonyl-2-amino-2-[2-(3-isoxazolylmethylthio)ethylamino]ethyleneand

1-(4-methylbenzene)sulphonyl-2-amino-2-[2-(3-isoxazolylmethylthio)ethylamino]ethylene.

EXAMPLE 371-Nitro-2-ethylamine-2-[2-(3-isoxazolylmethylthio)ethylamino]ethylene

Reaction of1-nitro-2-methylthio-2-[2-(3-isoxazolylmethylthio)ethylamino]ethylene(seeExample 31 (ii)) with ethylamine by the procedure of Example 8(ii)gives the title product.

EXAMPLE 38

Reaction of1-nitro-2-methylthio-2-[2-(3-isoxazolylmethylthio)ethylamino]ethylene inthe procedure of Example 3, with an excess of the following compounds:

3-[(2-aminoethyl)thiomethyl]isoxazole,

3-[(2-aminoethyl)thiomethyl]-1,2,4-triazole,

2-[(2-aminoethyl)thiomethyl]thiazole,

3-[(2-aminoethyl)thiomethyl]isothiazole (prepared by the method ofExample 72) and

2-amino-5-[(2-aminoethyl)thiomethyl]-1,3,4-thiadiazole, gives thefollowingproducts respectively:

1-nitro-2,2-bis-[2-(3-isoxazolylmethylthio)ethylamino]-ethylene,

1-nitro-2-[2-(3-isoxazolylmethylthio)ethylamino]-2-[2-(3-(1,2,4)-triazolylmethylthio)ethylamino]ethylene,

1-nitro-2-[2-(3-isoxazolylmethylthio)ethylamino]-2-[2-(2-thiazolylmethylthio)ethylamino]ethylene,

1-nitro-2-[2-(3-isoxazolylmethylthio)ethylamino]-2-[2-(3-isothiazolylmethylthio)ethylamino]ethyleneand

1-nitro-2-[2-(3-isoxazolylmethylthio)ethylamino]-2-[2-((2-amino-5-(1,3,4)-thiadiazolyl)methylthio]ethylamino]ethylene.

EXAMPLE 39

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        1-Nitro-2-methylamino-2-[2-(3-                                                isoxazolylmethylthio)ethylamino]ethylene                                                                150 mg                                              Sucrose                    75 mg                                              Starch                     25 mg                                              Talc                       5 mg                                               Stearic Acid               2 mg                                               ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 40

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        1-Nitro-2-methylamino-2-[2-(3-                                                isoxazolylmethylthio)ethylamino]ethylene                                                                200 mg                                              Lactose                   100 mg                                              ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 411-Nitro-2-methylamino-2-[2-(3-(1,2,4-triazolyl)methylthio)-ethylamino]ethylene

By the procedure of Example 8(i)3-[(2-aminoethyl)thiomethyl]-1,2,4-triazole (from the dihydrobromide(2.2 g)) is reacted with 1-nitro-2,2-bis-methylthioethylene (1.7 g) togive1-nitro-2-methylthio-2-[2-(3-(1,2,4)-triazolyl)methylthio)-ethylamino]ethylene(1.5 g) which on reaction with methylamine by the procedure ofExample8(ii) gives the title product (1.3 g)

EXAMPLE 42 1-Nitro-2-methylamino-2-[2-(4-methyl-3-(1,2,4-triazolyl)methylthio)ethylamino]ethylene

(i) Ethoxyacetyl chloride (57 g) was added slowly to a stirred solutionof 4-methylthiosemicarbizide (53.5 g) in dry pyridine (500 ml) at 0°-5°.The mixture was allowed to attain room temperature and stirring wascontinued for 18 hours. Following concentration under reduced pressurethe residue was treated with a solution of sodium (21.4 g) in ethanol(500 ml) and the mixture was heated under reflux for 24 hours. Followingconcentration and acidification with hydrochloric acid a solid wasobtained. After partial concentration the solid was collected andrecrystallised from ethyl acetate to give3-ethoxymethyl-4-methyl-1,2,4-triazoline-5-thione (53 g) m.p. 137°-138°.

The thione (44 g) was desulphurised by slow addition to a solutionpreparedfrom nitric acid (76 ml) water (150 ml) and sodium nitrite (1.5g) at 15°-20°. Following subsequent basification with sodium carbonateand concentration, the residue was extracted with ethanol-ether 1:1 anddistilled to afford 3-ethoxymethyl-4-methyl-1,2,4-triazole (30 g),b.p.154°-156°/0.05 mm. The above compound (15 g) dissolved in 48% aqueoushydrobromic acid (150 ml) was heated under reflux for 24 hours andconcentrated to dryness to give a mixture of4-methyl-3-bromomethyl-1,2,4-triazole and4-methyl-3-hydroxymethyl-1,2,4-triazole.

(ii) This mixture was reacted directly in solution in aqueoushydrobromic acid with cysteamine hydrochloride by heating under refluxovernight. After cooling, the solution was evaporated to dryness and theresidual solid washed with ethanol/ether to give3-[(2-aminoethyl)thiomethyl]-4-methyl-1,2,4-triazole dihydrobromide,m.p. 175°-177° C.

(iii) Using 3-[(2-aminoethyl)thiomethyl]-4-methyl-1,2,4-triazole (fromthe dihydrobromide) as the starting material in the procedure of Example41 yields the title product.

EXAMPLE 43

By the procedure of Example 42 (ii) and (iii), using the followingtriazoles as starting materials:

3-amino-5-hydroxymethyl-1,2,4-triazole,

3-bromo-5-hydroxymethyl-1,2,4-triazole and

3-(2-chloroethyl)-1,2,4-triazole

the products are, respectively,

1-nitro-2-methylamino-2-[2-(3-amino-5-(1,2,4-triazolyl)-methylthio)ethylamino]ethylene,

1-nitro-2-methylamino-2-[2-(3-bromo-5-(1,2,4-triazolyl)-methylthio)ethylamino]ethyleneand

1-nitro-2-methylamino-2-[2-(2-(3-(1,2,4-triazolyl)ethyl)-thio)ethylamino]ethylene.

EXAMPLE 441-Nitro-2-[2-((5-hydroxy-4-1,2,3-triazolyl)methylthio)ethylamino]2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene.

Alkaline hydrolysis of 5-hydroxy-4-carboethoxy-(1,2,3)triazole to thecorresponding carboxylic acid, conversion of the acid to the methylester and reduction of this ester with lithium aluminium hydride intetrahydrofuran gives 5-hydroxy-4-hydroxymethyl-(1,2,3)-triazole. Thiscompound is used as the starting material in the procedure of Example42(ii) to give 4-[(2-aminoethyl)thiomethyl]-5-hydroxy-1,2,3-triazolewhich, on reaction with2-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethyleneby the procedure of Example 3 yields the title product.

EXAMPLE 451-Nitro-2-methylamino-2-[4-(3-1,2,4-triazolyl)butylamino]ethylene

Use of 3-(4-aminobutyl)-1,2,4-triazole (from the dihydrochloride) as thestarting material in the procedure of Example 8(i) and (ii) results intheproduction of the title compound.

EXAMPLE 461-Nitro-2-methylamino-2-[3-(3-(1,2,4-triazolyl)thio)propylamino]ethylene.

(i) A solution of 3-mercapto-1,2,4-triazole and 3-aminopropanol inhydrobromic acid is heated under reflux for 24 hours. The reactionmixtureis evaporated to dryness and the residue recrystallised fromethanol/ether to give 3-(3-aminopropylthio)-1,2,4-triazoledihydrobromide.

(ii) Conversion of this dihydrobromide to the free base which is thenused as the starting material in the procedure of Example 8 (i) and 8(ii) yields the title product.

EXAMPLE 471,1-Dicyano-2-methylamino-2-[2-(3-(1,2,4-triazolyl)methylthio)-ethylamino]ethylene.

By the procedure of Example 1(ii), reacting3-[(2-aminoethyl)thiomethyl]-1,2,4-triazole with1,1-dicyano-2-methylthio-2-methylaminoethylene gives the title compound.

EXAMPLE 481-Cyano-2-methylamino-2-[2-(3-(1,2,4-triazolyl)methylthio)-ethylamino]ethylene.

By the same procedure as Example 7, using as starting material3-[(2-aminoethyl)thiomethyl]-1,2,4-triazole, the title compound isprepared.

EXAMPLE 49 Reaction of 3-[(2-aminoethyl)thiomethyl]-1,2,4-triazole bythe procedure ofExample 4 with the following acetonitriles:

phenylsulphonylacetonitrile,

(4-chlorophenyl)sulphonylacetonitrile,

(3,4-dichlorophenyl)sulphonylacetonitrile and

(4-methylphenyl)sulphonylacetonitrile

results in the formation of the following products, respectively:

1-benzenesulphonyl-2-amino-2-[2-(3-(1,2,4-triazolyl)-methylthio)ethylamino]ethylene,

1-(4-chlorobenzene)sulphonyl-2-amino-2-[2-(3-(1,2,4-triazolyl)methylthio)ethylamino]ethylene,

1-(3,4-dichlorobenzene)sulphonyl-2-amino-2-[2-(3-(1,2,4-triazolyl)methylthio)ethylamino]ethyleneand

1-(4-methylbenzene)sulphonyl-2-amino-2-[2-(3-(1,2,4-triazolyl)methylthio)ethylamino]ethylene.

EXAMPLE 501-Nitro-2-ethylamino-2-[2-(3-(1,2,4-triazolyl)methylthio)ethylamino]ethylen

Reaction of1-nitro-2-methylthio-2-[2-(3-(1,2,4-triazolyl)methylthio)ethylamino]ethylene(see Example 41) with ethylamine by the procedure of Example 8(ii)givesthe title product.

EXAMPLE 51

Reaction of1-nitro-2-methylthio-2-[2-(3-(1,2,4-triazolyl)-methylthio)ethylamino]ethylenein the procedure of Example 2(ii) with an excess of the followingcompounds:

3-[(2-aminoethyl)thiomethyl]-1,2,4-triazole,

2-[(2-aminoethyl)thiomethyl]thiazole,

3-[(2-aminoethyl)thiomethyl]isothiazole (prepared by the method ofExample 72) and

2-amino-5-[(2-aminoethyl)thiomethyl]-1,3,4-thiadiazole gives thefollowing products respectively:

1-nitro-2,2-bis-[2-(3-(1,2,4-triazolyl)methylthio)ethylamino]ethylene,

1-nitro-2-[2-(3-(1,2,4-triazolyl)methylthio)ethylamino]-2-[2-(2-thiazolylmethylthio)ethylamino]ethylene,

1-nitro-2-[2-(3-(1,2,4-triazolyl)methylthio)ethylamino]-2-[2-(3-isothiazolylmethylthio)ethylamino]ethyleneand

1-nitro-2-[2-(3-(1,2,4-triazolyl)methylthio)ethylamino]2-[2-((2-amino-5-(1,3,4)thiadiazolyl)methylthio)ethylamino]-ethylene.

EXAMPLE 52

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        1-Nitro-2-methylamino-2-[2-(3-(1,2,4-triazolyl)-                              methylthio)ethylamino]ethylene                                                                           150 mg                                             Sucrose                     75 mg                                             Starch                      25 mg                                             Talc                        5 mg                                              Stearic Acid                2 mg                                              ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 53

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        1-Nitro-2-methylamino-2-[2-(3-(1,2,4-triazolyl)-                              methylthio)ethylamino]ethylene                                                                           150 mg                                             Sucrose                     75 mg                                             Starch                      25 mg                                             Talc                        5 mg                                              Stearic Acid                2 mg                                              ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 54 1-Nitro-2,2-bis-[4-(2-thiazolyl)butylamino]ethylene

A mixture of 2-(4-aminobutyl)thiazole (from the dihydrobromide) (10.0 g)and 1-nitro-2,2-bis-methylthioethylene (3.0 g) in ethanol (20 ml) isheated under reflux for 3 hours. Concentration and treatment of theresidue with ether affords the title compound, m.p. 100°-110°(ethanol-ether).

EXAMPLE 551-Nitro-2-methylamino-2-[2-(2-thiazolylmethylthio)ethylamino]ethylene

(i) By the procedure of Example 8(i),2-[(2-aminoethyl)thiomethyl]thiazole (from the dihydrobromide, 4.0 g) isreacted with 1-nitro-2,2-bis methylthioethylene (2.0 g) to give1-nitro-2-methylthio-2-[(2-thiazolylmethylthio)ethylamino]ethylene, m.p.63°-64°.

(ii) Reaction of1-nitro-2-methylthio-2-[2-(2-thiazolylmethylthio)ethylamino]ethylenewith methylamine according to the process of Example 8(ii) yielded thetitle compound, m.p. 103°-104°. (from ethanol ether).

(Found :C, 39.4; H, 5.2; N,20.2% C₉ H₁₄ N₄ O₂ S₂ requires: C, 39.4; H,5.1; N, 20.4%).

EXAMPLE 561-Nitro-2-methylamino-2-[2-(4-thiazolylmethylthio)ethylamino]-ethylene

When 4-[(2-aminoethyl)thiomethyl]thiazole (from the dihydrobromide) isusedas the starting material in the procedure of Example 55, the titlecompoundis produced.

EXAMPLE 571-Nitro-2-methylamino-2-[3-(2-thiazolylthio)propylamino]ethylene

Using 2-(3-aminopropylthio)thiazole (from the dihydrobromide) as thestarting material in the procedure of Example 55 gives the titlecompound.

EXAMPLE 581-Nitro-2-methylamino-2-[2-(5-thiazolylmethylthio)ethylamino]-ethylene

When 5-[(2-aminoethyl)thiomethyl]thiazole (from the dihydrobromide) isusedas the starting material in the procedure of Example 55, the titlecompoundis produced.

EXAMPLE 591-Nitro-2-methylamino-2-[2-((2-amino-4-thiazolyl)methylthio)-ethylamino]ethylene

Using 2-amino-4-[(2-aminoethyl)thiomethyl]thiazole as the startingmaterialin the procedure of Example 55 gives the title compound.

EXAMPLE 60

Using the following thiazoles as starting materials in the procedure ofExample 42 (ii) and 42 (iii):

2-hydroxymethyl-4-methylthiazole,

4-chloromethyl-2-methylthiazole,

2-chloro-4-chloromethylthiazole and

4-(2-chloroethyl)thiazole

the products are, respectively:

1-nitro-2-methylamino-2-[2-((4-methyl-2-thiazolyl)-methylthio)ethylamino]ethylene,

1-nitro-2-methylamino-2-[2-((2-methyl-4-thiazolyl)-methylthio)ethylamino]ethylene,

1-nitro-2-methylamino-2-[2-((2-chloro-4-thiazolyl)-methylthio)ethylamino]ethyleneand

1-nitro-2-methylamino-2-[2-(2-(4-thiazolyl)ethyl)-thioethylamino]ethylene.

EXAMPLE 611-Nitro-2-[2-((2-hydroxy-4-thiazolyl)methylthio]ethylamino]-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene

2-Hydroxy-4-thiazolecarboxylic acid is converted to the methyl ester andthe ester is reduced with lithium aluminium hydride in tetrahydrofuranto give 2-hydroxy-4-hydroxymethylthiazole. This compound is used as thestarting material in the procedure of Example 42 (ii) to give2-hydroxy-4-[(2-aminoethyl)thiomethyl]thiazole which, on reaction with1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethyleneby the procedure of Example 3 yields the title compound.

EXAMPLE 62 1-Nitro-2-methylamino-2-[4-(2-thiazolyl)butylamino]ethylene

Using 2-(4-aminobutyl)thiazole as the starting material in the procedureofExample 55 results in the production of the title compound, m.p.144°-145° (ethanol-ether).

EXAMPLE 631,1-Dicyano-2-methylamino-2-[2-(2-thiazolylmethylthio)-ethylamino]ethylene

By the procedure of Example 1(ii), reacting2-[(2-aminoethyl)-thiomethyl]thiazole with1,1-dicyano-2-methylthio-2-methylaminoethylene gives the title compound.

EXAMPLE 641-Cyano-2-methylamino-2-[2-(2-thiazolylmethylthio)ethylamino]-ethylene

By the same procedure as Example 7, using as starting material2-[(2-aminoethyl)thiomethyl]thiazole, the title compound is prepared.

EXAMPLE 65

Reaction of 2-[(2-aminoethyl)thiomethyl]thiazole by the procedure ofExample 4 with the following acetonitriles:

phenylsulphonylacetonitrole,

(4-chlorophenyl)sulphonylacetonitrile,

(3,4-dichlorophenyl)sulphonylacetonitrile and

(4-methylphenyl)sulphonylacetonitrile

results in the formation of the following products, respectively:

1-benzenesulphonyl-2-amino-2-[2-(2-thiazolylmethylthio)-ethylamino]ethylene

1-(4-chlorobenzene)sulphonyl-2-amino-2-[2-(2-thiazolylmethylthio)ethylamino]ethylene,

1-(3,4-dichlorobenzene)sulphonyl-2-amino-2-[2-(2-thiazolylmethylthio)ethylamino]ethyleneand

1-(4-methylbenzene)sulphonyl-2-amino-2-[2-(2-thiazolylmethylthio)ethylamino]ethylene

EXAMPLE 661-Nitro-2-ethylamino-2-[2-(2-thiazolylmethylthio)ethylamino]ethylene.

Reaction of1-nitro-2-methylthio-2-[2-(2-thiazolylmethylthio)-ethylamino]ethylene(seeExample 55(i)) with ethylamine by the procedure of Example 8(ii)gives the title product, m.p. 115°-116° (from water).

EXAMPLE 671-Nitro-2,2-bis-[2-(2-thiazolylmethylthio)ethylamino]-ethylene

A mixture of 2-[(2-aminoethyl)thiomethyl]thiazole (from thedihydrobromide 4.0 g) and 1-nitro-2,2-bis-methylthioethylene (0.99 g)was heated at 100° for 2 hours. Crystallisation of the reaction productfrom ethanolether yields the title compound, m.p. 50°-51°.

(Found: C, 39.6; H, 4.6; N, 16.4%. C₁₄ H₁₉ N₅ O₂ S₄ requires: C, 40.2;H, 4.6; N, 16.8%).

EXAMPLE 68

Reaction of1-nitro-2-methylthio-2-[(2-thiazolylmethylthio)ethylamino]ethylene inthe procedure of Example 2(ii) with excess of the following compounds:

3-[(2-aminoethyl)thiomethyl]isothiazole (prepared by the method ofExample 72) and

2-amino-5-[(2-aminoethyl)thiomethyl]-1,3,4-thiadiazole

gives the following products respectively:

1-nitro-2-[2-(2-thiazolylmethylthio)ethylamino]-2-(3-isothiazolylmethylthio)ethylamino]ethyleneand

1-nitro-2-[2-(2-thiazolylmethylthio)ethylamino]-2-[2-((2-amino-5-(1,3,4)thiadiazolyl)methylthio)ethylamino]ethylene.

EXAMPLE 69

When a solution of1-nitro-2-[2-(2-thiazolylmethylthio)ethylamino]-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylenein acetone is treated with ion-exchange resin IRA 400 in the chlorideform the corresponding hydrochloride addition salt is formed.

Similarly, by using the above procedure with ion-exchange resin IRA 400which has been converted to the bromide, iodide and sulphaterespectively the hydrobromide, hydriodide and hydrogen sulphate additionsalts of1-nitro-2-[2-((2-2-thiazolyl)methylthio)ethylamino]-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylenemay be produced.

EXAMPLE 70

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        1-Nitro-2-methylamino-2-[2-(2-thiazolyl-                                      methylthio)ethylamino]ethylene                                                                          150 mg                                              Sucrose                    75 mg                                              Starch                     25 mg                                              Talc                       5 mg                                               Stearic Acid               2 mg                                               ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 71

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        1-Nitro-2,2-bis-[2-(2-thiazolylmethylthio)-                                   ethylamino]ethylene        200 mg                                             Lactose                    100 mg                                             ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 721-Nitro-2-methylamino-2-[2-(3-isothiazolylmethylthio)-ethylamino]ethylene.

(i) A solution was prepared by the gradual addition of cysteaminehydrochloride (2.03 g) to sodium (0.83 g) dissolved in ethanol (50 ml)with stirring at 0° under a nitrogen atmosphere. After stirring for2hours at 0° 3-bromomethylisothiazole (3.2 g) was added dropwise over 15minutes at 0°, the reaction mixture subsequently being set asideovernight at room temperature. Following acidification to pH 3.5 withhydrochloric acid, concentration and re-evaporation with ethanol,theresidue was dissolved in ethanol, filtered and concentrated to yield3-[(2-aminoethyl)thiomethyl]isothiazole hydrochloride (3.5 g). This wasconverted directly to the free base by treatment with aqueous potassiumcarbonate and extraction with ether. The extracts were dried overmagnesium sulphate, dried and concentrated to yield the amine base as anoil (1.56 g).

(ii) By the procedure of Example 8(i), this amine base is reacted with1-nitro-2,2-bis-methylthioethylene to give1-nitro-2-methylthio-2-[2-(3-isothiazolylmethylthio)ethylamino]-ethylenem.p. 64.5°-65.5°. Reaction of this compound with methylamineaccording tothe process of Example 8(ii) yields the title compound, m.p.118.5°-119.5° (from ethanol-toluene).

EXAMPLE 731-Nitro-2-methylamino-2-[(2-((4-bromo-3-isothiazolyl)methylthio)ethylamino]ethylene

(i) The reaction of 4-bromo-3-(bromomethyl)isothiazole (8.5 g) withcysteamine (from cysteamine hydrochloride (3.76 g)) was performed underconditions similar to those described in Example 72. From the reactionthere was obtained 4-bromo-3-[(2-aminoethyl)thiomethyl]isothiazolehydrobromide, which, following recrystallisation from ethanol-ether andacetonitrile, gave needles (4.05 g), m.p. 111°-112°. The amine base(2.73 g) was isolated by basification with sodium hydroxideandextraction with chloroform.

(ii) Use of the amine base as the starting material in the procedure ofExample 72(ii) gives the title compound.

EXAMPLE 74

Using the following halomethylisothiazole as starting material in theprocedure of Example 72:

3-bromomethyl-4-chloroisothiazole

the product is:

1-nitro-2-methylamino-2-[2-((4-chloro-3-isothiazolyl)-methylthio)ethylamino]ethylene.

EXAMPLE 751-Nitro-2-methylamino-2-[2-((3-methyl-4-isothiazolyl)-methylthio)ethylamino]ethylene.

Reacting 4-hydroxymethyl-3-methylisothiazole (3.0 g) with cysteaminehydrochloride (2.8 g) in 48% aqueous hydrobromic acid (50 ml) by theprocedure of Example 42(ii) gives3-methyl-4-[(2-aminoethyl)thiomethyl]isothiazole hydrobromide. The baseisobtained by basifying with aqueous potassium carbonate, extractingwith chloroform, drying the extracts over magnesium sulphate andconcentrating.Using the amine (5.0 g) as the starting material in theprocedure of Example 72(ii) yields the title compound.

EXAMPLE 761-Nitro-2-methylamino-2-[2-(2-(3-isothiazolyl)ethylthioethylamino]ethylene

3-Isothiazoleacetic acid is converted to the methyl ester and the esteris reduced with lithium aluminium hydride in tetrahydrofuran to give3-(2-hydroxyethyl)isothiazole. Reacting this hydroxyethyl compound withthionyl chloride gives 3-(2-chloroethyl)isothiazole. Using3-(2-chloroethyl)-isothiazole in the procedure of Example 72 (i) and(ii),gives the title compound.

EXAMPLE 771-Nitro-2-methylamino-2-[3-(3-isothiazolylmethylthio)propylamino]ethylene.

When, in the procedure of Example 72, cysteamine hydrochloride isreplaced by 3-mercaptopropylamine hydrochloride, the title compound isproduced.

EXAMPLE 781,1-Dicyano-2-methylamino-2-[2-(3-isothiazolylmothylthio)ethylamino]ethylen

By the procedure of Example 1(ii), reacting3-[(2-aminoethyl)thiomethyl]isothiazole with1,1-dicyano-2-methylthio-2-methylaminoethylene gives the title compound.

EXAMPLE 791-Cyano-2-methylamino-2-[2-(3-isothiazolylmethylthio)ethylamino]ethylene.

By the same procedure as Example 7, using as starting material3-[(2-aminoethyl)thiomethyl]isothiazole, the title compound is prepared.

EXAMPLE 80

Reaction of 3-[(2-aminoethyl)thiomethyl]isothiazole by the procedure ofExample 4 with the following acetonitriles:

phenylsulphonylacetonitrole,

(4-chlorophenyl)sulphonylacetonitrile,

(3,4-dichlorophenyl)sulphonylacetonitrile and

(4-methylphenyl)sulphonylacetonitrile

results in the formation of the following products, respectively:

1-benzenesulphonyl-2-amino-2-[2-(3-isothiazolyl)methylthio)-ethylamino]ethylene,

1-(4-chlorobenzene)sulphonyl-2-amino-2-[2-(3-isothiazolylmethylthio)ethylamino]ethylene,

1-(3,4-dichlorobenzene)sulphonyl-2-amino-2-[2-(3-isothiazolylmethylthio)ethylamino]ethyleneand

1-(4-methylbenzene)sulphonyl-2-amino-2-[2-(3-isothiazolylmethylthio)ethylamino]ethylene.

EXAMPLE 811-Nitro-2-ethylamino-2-[2-(3-isothiazolylmethylthio)ethylamino]ethylene

Reaction of1-nitro-2-methylthio-2-[2-(3-isothiazolylmethylthio)ethylamino]ethylene(see Example 72(ii) with ethylamine by the procedure of Example 8(ii)gives the title product.

EXAMPLE 82

Reaction of1-nitro-2-methylthio-2-[2-(3-isothiazolylmethylthio)ethylamino]ethyleneinthe procedure of Example 2(ii) with an excess of the followingcompounds:

3-[(2-aminoethyl)thiomethyl]isothiazole and

2-amino-5-[(2-aminoethyl)thiomethyl]-1,3,4-thiadiazole gives thefollowing products respectively:

1-nitro-2,2-bis[2-(3-isothiazolylmethylthio)ethylamino]ethylene and

1-nitro-2-[2-(3-isothiazolylmethylthio)ethylamino]-2-[2-((2-amino-5-(1,3,4)thiadiazolyl)methylthio)ethylamino]ethylene.

EXAMPLE 83

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        1-Nitro-2-methylamino-2-[2-(3-isothiazolyl-                                   methylthio)ethylamino]ethylene                                                                           150 mg                                             Sucrose                     75 mg                                             Starch                      25 mg                                             Talc                        5 mg                                              Stearic Acid                2 mg                                              ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 84

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        1-Nitro-2-methylamino-2-[2-((4-bromo-                                         3-isothiazolyl)methylthio)ethylamino]ethylene                                                            200 mg                                             Lactose                    100 mg                                             ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 851-Nitro-2-methylamino-2-[2-((2-amino-5-(1,3,4)-thiadiazolyl)-methylthio)ethylamino]ethylene

(i) By the procedure of Example 8(i),2-amino-5-(2-aminoethyl)thiomethyl-1,3,4-thiadiazole (from thedihydrobromide) is reacted with 1-nitro-2,2-bis-methylthioethylene togive1-nitro-2-methylthio-2-[2-((2-amino-5-(1,3,4)-thiadiazolyl)methylthio)ethylamino]ethylene.

(ii) Reaction of this compound with methylamine according to the processofExample 8(ii) gives the title compound.

EXAMPLE 86

Addition of phosphonyl chloride to a mixture of thiosemicarbazide andmethoxyacetic acid at 60°-95° and working up of the product yields5-amino-2-methoxymethyl-(1,3,4)-thiadiazole, m.p. 177°-179° (fromwater). When this compound is diazotised andtreated with cuprous bromide5-bromo-2-methoxymethyl-(1,3,4)-thiadiazole results and reaction of thisbromo compound with zinc dust in acetic acid at room temperature yields2-methoxymethyl-(1,3,4)-thiadiazole, m.p. 30.5°-32°.

Using the following thiadiazoles as starting materials in the procedureof Example 42(ii) and 42(iii):

5-chloro-3-chloromethyl-1,2,4-thiadiazole and2-methoxymethyl-1,3,4-thiadiazole

the products are, respectively:

1-nitro-2-methylamino-2-[2-((5-chloro-3-1,2,4-thiadiazolyl)methylthio)ethylamino]ethyleneand

1-nitro-2-methylamino-2-[2-((2-1,3,4-thiadiazolyl)methylthio)ethylamino]ethylene.

EXAMPLE 871-Nitro-2-methylamino-2-[2-((3-1,2,5-thiadiazolyl)methylthio)ethylamino]ethylene.

Reaction of 3-methyl-1,2,5-thiadiazole with N-bromosuccinimide resultsin the production of 3-bromomethyl-1,2,5-thiadiazole.

When 3-bromomethyl-1,2,5-thiadiazole is used as the starting material inthe procedure of Example 42(ii) and 42(iii). the title compound isproduced.

EXAMPLE 881-Nitro-2-methylamino-2-[2-(2-(2-amino-5-(1,3,4)-thiadiazolyl)ethylthio)ethylamino]ethylene

2-Amino-5-(1,3,4-thiadiazole)acetic acid is esterified with anhydrousethanolic hydrogen chloride and the resulting ethyl ester is reducedwith lithium aluminium hydride in tetrahydrofuran to give2-amino-5-(2-hydroxyethyl)-1,3,4-thiadiazole. Treating this hydroxyethylcompound with thionyl chloride gives2-amino-5-(2-chloroethyl)-1,3,4-thiadiazole.

Using 2-amino-5-(2-chloroethyl)-1,3,4-thiadiazole as the startingmaterial in the procedure of Example 42(ii) and 42(iii) gives the titlecompound.

EXAMPLE 891-Nitro-2-methylamino-2-[3-(2-amino-5-(1,3,4-thiadiazolyl)thio)propylamino]ethylene

Using 2-amino-5-(3-aminopropylthio)-1,3,4-thiadiazole (from thedihydrobromide) as the starting material in the procedure of Example8(i) and (ii) gives the title compound.

EXAMPLE 901,1-Dicyano-2-[2-((2-amino-5-(1,3,4)-thiadiazolyl)methylthio)-ethylamino]-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene

By the procedure of Example 24(iii) reacting2-amino-5-[(2-aminoethyl)thiomethyl]-1,3,4-thiadiazole with1,1-dicyano-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-ethylene,gives the title compound.

EXAMPLE 911-Cyano-2-[2-((2-amino-5-(1,3,4)-thiadiazolyl)methylthio)ethylamino]-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-ethylene.By the same procedure as Example 25(ii) using as starting material2-amino-5-[(2-aminoethyl)thiomethyl]-1,3,4-thiadiazole, the titlecompoundis prepared. EXAMPLE 92

Reaction of 2-amino-5-[(2-aminoethyl)thiomethyl]-1,3,4-thiadiazole bythe procedure of Example 4 with the following compounds:

1-benzenesulphonyl-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene,

1-(4-chlorobenzene)sulphonyl-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene,

1-(3,4-dichlorobenzene)sulphonyl-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethyleneand

1-(4-methylbenzene)sulphonyl-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene,

results in the formation of the following products respectively:

1-benzenesulphonyl-2-[2-((2-amino-5-1,3,4-thiadiazolyl)-methylthio)ethylamino]-2-[2-((4-methyl-5-imidazolyl)-methylthio)ethylamino]ethylene,

1-(4-chlorobenzene)sulphonyl-2-[2-((2-amino-5-1,3,4-thiadiazolyl)methylthio)ethylamino]-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene,

1-(3,4-dichlorobenzene)sulphonyl-2-[2-((2-amino-5-1,3,4-thiadiazolyl)methylthio)ethylamino]-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethyleneand

1-(4-methylbenzene)sulphonyl-2-[2-((2-amino-5-1,3,4-thiadiazolyl)methylthio)ethylamino]-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene.

EXAMPLE 931-Nitro-2-ethylamino-2-[3-((2-amino-5-1,3,4-thiadiazolyl)-methylthio)ethylamino]ethylene

Reaction of1-nitro-2-methylthio-2-[2-((2-amino-5-(1,3,4)-thiadiazolyl)methylthio)ethylamino]ethylene(see Example 85(i)) with ethylamine by the procedure of Example 8(ii)gives the title product.

EXAMPLE 941-Nitro-2,2-bis-[2-((2-amino-5-1,3,4-thiadiazolyl)methylthio)ethylamino]ethylene

When 2-amino-5-[(2-aminoethyl)thiomethyl]-1,3,4-thiadiazole is used asthe starting material in the process of Example 67, the title compoundis produced.

EXAMPLE 95

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        1-Nitro-2-methylamino-2-[2-((2-amino-5-1,3,4-                                 thiadiazolyl)methylthio)ethylamino]ethylene                                                              150 mg                                             Sucrose                     75 mg                                             Starch                      25 mg                                             Talc                        5 mg                                              Stearic Acid                2 mg                                              ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 96

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        1-Nitro-2-methylamino-2-[3-((2-amino-5-                                       1,3,4-thiadiazolyl)thio)propylamino]ethylene                                                             200 mg                                             Lactose                    100 mg                                             ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 97

When, in the procedure of Example 14, the following compounds arereacted with 1,1 -diphenylsulphenyl-2-methylthio-2-methylaminoethylene:

2-[3-aminopropylthio]oxazole,

3-[(2-aminoethyl)thiomethyl]isoxazole,

3-[(2-aminoethyl)thiomethyl]-1,2,4-triazole,

2-[(2-aminoethyl)thiomethyl]thiazole,

3-[(2-aminoethyl)thiomethyl]isothiazole and

2-amino-5-[(2-aminoethyl)thiomethyl]-1,3,4-thiadiazole

the products are:

1,1-diphenylsulphonyl-2-methylamino-2-[3-(2-oxazolylthio)propylamino]ethylene.

1,1-diphenhlsulphonyl-2-methylamino-2-[2-(3-isoxazolylmethylthio)ethylamino]ethylene,

1,1-diphenylsulphonyl-2-methylamino-2-[2-(3-(1,2,4-triazolyl)methylthio)ethylamino]ethylene,

1,1-diphenylsulphonyl-2-methylamino-2-[2-(2-thiazolylmethylthio)ethylamino]ethylene,

1,1-diphenylsulphonyl-2-methylamino-2-[2-(3-isothiazolylmethylthio)ethylamino]ethyleneand

1,1-diphenylsulphonyl-2-methylamino-2-[2-((2-amino-5-1,3,4-thiadiazolyl)methylthio)ethylamino]ethylene.

By the same procedure, starting from:

1-cyano-1-nitro-2-methylthio-2-methylaminoethylene,

1-nitro-1-phenylsulphonyl-2-methylthio-2-methylaminoethylene and

1-cyano-1-phenylsulphonyl-2-methylthio-2-methylaminoethylene

the corresponding products in which the 2-methylthio group has beendisplaced by a:

2-[3-(2-oxazolylthio)propylamino],

2-[2-(3-isoxazolylmethylthio)ethylamino],

2-[2-(3-(1,2,4-triazolyl)methylthio)ethylamino],

2-[2-(2-thiazolylmethylthio)ethylamino],

2-[2-(3-isothiazolylmethylthio)ethylamino] or

2-[2-((2-amino-5-1,3,4-thiadiazolyl)methylthio)-ethylamino]

group may be prepared.

EXAMPLE 981-Nitro-2-amino-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene

Reaction of1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene(see Example 2(i)) with ammonia by the procedure of Example 2(ii)yields, after recrystallisation from methanol, the title compound, m.p.193°-195° C.

EXAMPLE 99 1-Nitro-2,2-bis-[4-(5-bromo-4-imidazolyl)butylamino]ethylene

Reaction of 5-bromo-4-(4-aminobutyl)imidazole with1-nitro-2,2-bis-methylthioethylene in the procedure of Example 8(i)yields1-nitro-2-methylthio-2-[4-(4-imidazolyl)butylamino]-ethylene, m.p.157°-158°, (from isopropanol).

(ii) When this methylthio compound is reacted with5-bromo-4-(4-aminobutyl)imidazole in the procedure of Example 8(ii), thetitle compound is produced, m.p. 198°-199.5° (from ethanol).

EXAMPLE 1001-Nitro-2-methylamino-2-[4-(5-bromo-4-imidazolyl)butylamino]-ethylene

When 5-bromo-4-(4-aminobutyl)imidazole is reacted with1-nitro-2,2-bis-methylthioethylene according to the procedure of Example8(i) and the resultant1-nitro-2-methylthio-2-[4-(5-bromo-4-imidazolyl)butylamino]ethylene,m.p. 157°-158° treated with methylamine by the procedure of Example8(ii), the title compound, m.p. 145°-148° is produced.

We claim:
 1. A compound of the formula: ##STR8## wherein X and Y, whichmay be the same or different, are hydrogen, nitro, cyano or SO₂ Ar butare not both hydrogen; Het' is an oxazole or isoxazole ring which ringis attached at a ring carbon and is unsubstituted or substituted bylower alkyl, hydroxyl, halogen or amino; R is hydrogen, lower alkyl orHet-(CH₂)_(m) Z(CH₂)_(n) ; Z is sulphur or methylene; m is 0, 1 or 2 andn is 2 or 3 provided that the sum of m and n is 3 or 4; Het is anoxazole, isoxazole or triazole ring which ring is attached at a ringcarbon and is unsubstituted or substituted by lower alkyl, hydroxyl,halogen or amino; and Ar is phenyl unsubstituted or substituted byhalogen or methyl or a pharmaceutically acceptable acid addition saltthereof.
 2. A compound of claim 1 wherein X and Y are hydrogen, nitro orcyano, but are not both hydrogen; and R is hydrogen or lower alkyl.
 3. Acompound of claim 1 wherein R is methyl or Het-CH₂ SCH₂ CH₂ : Z issulphur: m is 1 and n is
 2. 4. A compound of claim 1 wherein X is nitroand Y is hydrogen.
 5. A pharmaceutical composition to inhibit H-2histamine receptors comprising a pharmaceutical carrier and in aneffective amount to inhibit said receptors a compound of claim
 1. 6. Amethod of inhibiting H-2 histamine receptors which comprisesadministering to an animal in need thereof in an effective amount toinhibit said receptors a compound of claim 1.